1. Technical Field
The present invention relates generally to systems for high speed synthesis and analysis of combinatorial libraries by contacting library members, simultaneously or in rapid serial fashion, with a test fluid, and more particularly, to an apparatus and method for making libraries of mixed inorganic oxides and for screening library members based on each member""s ability to catalyze the conversion of fluid reactants.
2. Discussion
Combinatorial chemistry refers to methods for creating chemical librariesxe2x80x94vast collections of compounds of varying propertiesxe2x80x94that are tested or screened in order to identify a subset of promising compounds. Depending on how they are made, libraries may consist of substances free in solution, bound to solid supports, or arrayed on a solid surface.
The advent of combinatorial chemistry promises to change the discovery and development of new and useful materials. For example, workers in the pharmaceutical industry have successfully used such techniques to dramatically increase the speed of drug discovery. Material scientists have employed combinatorial methods to develop novel high temperature superconductors, magnetoresistive materials, and phosphors. More recently, scientists have applied combinatorial methods to catalyst development. See, for example, copending U.S. patent application Ser. No. 08/327,513 xe2x80x9cThe Combinatorial Synthesis of Novel Materialsxe2x80x9d (published as WO 96/11878) and copending U.S. patent application Ser. No. 08/898,715 xe2x80x9cCombinatorial Synthesis and Analysis of Organometallic Compounds and Catalystsxe2x80x9d (published as WO 98/03521), which are both herein incorporated by reference.
Once a researcher creates a combinatorial library, he or she must screen tens, hundreds or even thousands of compounds. Existing analytical methods and devices, which were originally designed to characterize a relatively small number of compounds, are often ill-suited to screen combinatorial libraries. This is true in catalyst research where, up until now, there has been little need to rapidly test or characterize large numbers of compounds at one time.
In traditional catalyst development, for example, researchers synthesize relatively large amounts of a candidate compound. They then test the compound to determine whether it warrants further study. For solid phase catalysts, this initial testing involves confining the compound in a pressure vessel, and then contacting the compound with one or more fluid phase reactants at a particular temperature, pressure and flow rate. If the compound produces some minimal level of reactant conversion to a desired product, the compound undergoes more thorough characterization in a later step.
Because synthesis consumes a large fraction of the development cycle in traditional catalyst studies, researchers have expended little effort to speed up the screening step. Thus, although test reactors have been steadily improved over the years, most were simply automated to reduce labor needed to operate them. Even automated catalyst screening devices comprised of multiple reaction vessels were operated sequentially, so that the reaction time for a group of candidate compounds was about the same as could be achieved with a single-vessel reactor.
Conventional catalyst screening devices have other problems as well. For example, traditional experimental fixed bed reactors require relatively large catalyst samples. This makes them impracticable for screening combinatorial libraries. With combinatorial methods, one obtains increased chemical diversity at the expense of sample size. Individual library members may therefore consist of no more than a milligram (mg) or so of material. In contrast, conventional fixed bed reactors typically require 10 g or more of each candidate compound.
The present invention overcomes, or at least minimizes, one or more of the problems set forth above.
In accordance with one aspect of the present invention, there is provided an apparatus for screening members of a combinatorial library by contacting library members with a test fluid. The apparatus includes a plurality of vessels for receiving the library members, a detector for analyzing changes in test fluid following contact with library members, and a fluid handling system that is designed to apportion test fluid about equally between each of the vessels. The fluid handling system comprises an entrance control volume and an exit control volume that are in fluid communication with the inlets and the outlets of the vessels, respectively. A plurality of flow restrictors provide fluid communication between the vessels and either the entrance control volume or the exit control volume. During screening, a higher pressure is maintained in the entrance control volume than in the exit control volume so that test fluid flows from the entrance control volume to the exit control volume through the vessels. The test fluid is split about equally between each vessel because the resistance to fluid flow is greatest in the flow restrictors, varies little between individual flow restrictors, and is much larger than resistance to fluid flow in the vessels and other components of the fluid handling system.
In accordance with a second aspect of the present invention, there is provided an apparatus for screening members of a combinatorial library by simultaneously contacting library members with a test fluid. The apparatus includes a plurality of vessels for receiving the library members, a detector for analyzing changes in test fluid following contact with library members, and a fluid handling system that is designed to apportion test fluid about equally between each of the vessels. The fluid handling system comprises an entrance control volume, and a plurality of flow restrictors that provide fluid communication between the vessel inlets and the entrance control volume. The fluid handling system also includes a plurality of outlet conduits and a selection valve, the outlet conduits providing fluid communication between the vessel outlets and the selection valve. The selection valve is adapted to divert fluid from a selected vessel to a sample bypass while allowing fluid from non-selected vessels to flow to an exit control volume via a common exhaust port. A return line vents most of the test fluid in the sample bypass into the exit control volume, though a small fraction is sent to the detector for analysis. Fluid in the sample bypass is split between the exit control volume and detector using a sampling valve, which provides selective fluid communication between the sample bypass and the exit control volume, and between the sample bypass and the detector. During screening, a higher pressure is maintained in the entrance control volume than in the exit control volume so that test fluid flows from the entrance control volume to the exit control volume through the vessels. The test fluid is split about equally between each vessel because the resistance to fluid flow is greatest in the flow restrictors, varies little between individual flow restrictors, and is much larger than resistance to fluid flow in the other components of the fluid handling system.
In accordance with a third aspect of the present invention, there is provided a reactor for evaluating catalytic performance of members of a combinatorial library by contacting library members with a reactive fluid. The apparatus includes a plurality of vessels for receiving the library members, and a fluid handling system that is designed to apportion the reactive fluid about equally between each of the vessels. The fluid handling system comprises an entrance control volume and an exit control volume that are in fluid communication with the inlets and outlets of the vessels, respectively. A plurality of flow restrictors provide fluid communication between the vessels and either the entrance control volume or the exit control volume. During screening, a higher pressure is maintained in the entrance control volume than in the exit control volume so that test fluid flows from the entrance control volume to the exit control volume through the vessels. The reactive fluid is split about equally between each vessel because the resistance to fluid flow is greatest in the flow restrictors, varies little between individual flow restrictors, and is much larger than resistance to fluid flow elsewhere in the fluid handling system.
In accordance with a fourth aspect of the present invention, there is provided a method of screening members of a combinatorial library comprising the steps of confining about equal amounts of a group of library members in a plurality of vessels, contacting each of the confined library members with a test fluid by flowing the test fluid through each of the vessels, and detecting changes in the test fluid following contact with each of the confined library members. Changes in the test fluid are then related to a property of interest, such as catalytic activity and selectivity. The contacting step and the detecting step are carried out for at least two of the confined library members simultaneously, and the amount of test fluid flowing through each of the vessels per unit time is about the same.
A fifth aspect of the present invention provides a method of making a mixed inorganic oxide. In accordance with the method, metal precursors and polymer are dissolved in a solvent (ordinarily water) to form a metal-rich solution. The metal-rich solution is dried, typically by lyophilization, and then calcined, resulting in the mixed inorganic oxide. The mixed inorganic oxide can then be screened for various properties by contacting it with a test fluid. The metal precursors are salts of transition metals, alkaline earth metals or lanthanide series metals, either alone or in combination. Examples include salts of Ni, Co, Fe, Cr, Mn, Zn, Cd, V, Ca, Mg, Ba, Sr, Ce, Eu, In, Pb, Sn, and Bi. Useful polymers generally include those having polar functionalities that bind metal or metalloid ions and prevent the ions from precipitating out of the metal-rich solution. Examples include poly(acrylic acid), polyvinyl alcohol, polyvinyl acetate, ethylene vinyl alcohol, ethylene vinyl acetate and the like. The metal-rich solutionsxe2x80x94i.e., metal concentrations greater than about 0.5 Mxe2x80x94allows one to prepare relatively large amounts of oxide mixtures in small volumes.
A sixth aspect of the present invention provides an in-situ method of preparing and screening mixtures of inorganic oxides. The method includes the step of loading vessels with portions of stock solutions, each stock solution comprised of a metal precursor dissolved in solvent. The various stock solutions are combined in proper volumetric ratios to achieve the requisite metal composition in each of the vessels. The mixtures of metal precursors are dried, usually by evaporization or lyophilization, and then calcined at elevated temperature to fully oxidize the metal precursors. The resulting mixed inorganic oxides are analyzed or screened by contacting each mixture with a test fluid. One can then relate changes detected in the test fluid following contact with the samples to one or more properties of the mixed inorganic oxides. For example, the ability of a mixed inorganic oxide to catalyze a given reaction can be evaluated by detecting the disappearance or appearance, respectively, of a reactant or product in the test fluid. An advantage of the present method is that synthesis and analysis of the inorganic oxides occur in the same vessels, which results in significant time and labor savings in comparison to conventional methods.
An important aspect of in-situ synthesis and analysis is that the vessels must allow test fluid to flow through the mixed oxides during the contacting step, but must prevent the flow of the liquid metal precursors out of the vessels during loading and subsequent drying of the liquid-phase metal precursors. A useful approach is to block each of the vessel outlets with a fluid permeable barrierxe2x80x94one or more layers of quartz paper, for examplexe2x80x94which prevents the passage of the mixed inorganic oxides through the vessel outlets. A removable seal is disposed on the fluid permeable barrier and inhibits the passage of the liquid-phase metal precursors through the vessel outlets prior to converting the liquid-phase metal precursors into the mixed inorganic oxides. Typically, the removable seal is a heat labile material that is dimensionally stable at temperatures associated with vessel loading and drying, but decomposes at calcining temperatures. Heat labile materials include cellulose, low molecular weight polyolefins, and paraffin (wax).